WO2010023705A1 - Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders - Google Patents

Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders Download PDF

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WO2010023705A1
WO2010023705A1 PCT/IT2009/000392 IT2009000392W WO2010023705A1 WO 2010023705 A1 WO2010023705 A1 WO 2010023705A1 IT 2009000392 W IT2009000392 W IT 2009000392W WO 2010023705 A1 WO2010023705 A1 WO 2010023705A1
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enhancers
riboflavin
wt
corneal
use according
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PCT/IT2009/000392
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French (fr)
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Marcello Stagni
Edoardo Stagni
Massimo Filippello
Giovanni Cavallo
Eugenio Sodo
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Sooft Italia Spa
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/14Quaternary ammonium compounds, e.g. edrophonium, choline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/473Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/49Cinchonan derivatives, e.g. quinine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/54Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/60Salicylic acid; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears

Abstract

Described herein is the use of enhancers with possibly riboflavin, as well as the corresponding compositions for the treatment of keratoconus or other ectasic corneal disorders by means of the method of corneal cross-linking.

Description

"USE OF ENHANCERS, POSSIBLY ASSOCIATED TO RIBOFLAVIN, AS WELL AS CORRESPONDING OPHTHALMIC COMPOSITIONS FOR CORNEAL CROSS-LINKING IN THE TREATMENT OF THE KERATOCONUS OR OF OTHER CORNEAL ECTASIC DISORDERS"

The present invention relates to the use of enhancers for the preparation of ophthalmic compositions (in particular collyriums) possibly containing riboflavin, designed to imbibe the corneal stroma without having to proceed, in order to obtain said imbibition, to the removal of the corneal epithelium (de-epithelization) in the practice of the treatment of keratoconus, or other ectasic corneal disorders, by means of cross-linking, and also relates to the corresponding ophthalmic compositions for the technique of corneal cross-linking.

Keratoconus is a serious disease of the cornea since it is a non-inflammatory progressive dystrophy that each year affects approximately 50 persons in every 100 000, generally young people of between 10 and 20 years of age. Keratoconus is a genetic disease with a higher frequency amongst females and at times appears to be correlated to dysfunctions of endocrine glands (hypophysis and thyroid) . It can affect both eyes in approximately 85% of cases and has an evolution that may vary from subject to subject.

Upon onset of this disease, there appears an irregular curvature that modifies the refractive power of the cornea, producing distorsions of images and a confused close and distant vision. The patient complains in any case of a reduction of vision, above all distant^ vision. The vision continues to regress irreversibly, with a consequent need for frequent change of spectacles, and for this reason it may at first be mistaken for a myopia associated to astigmatism.

On account of the congenital structural weakness of the corneal stroma due to said disease, after some years the cornea progressively tends to wear out and thin out towards the apex. There then occurs an irregular curvature of the cornea, which loses its spherical shape and assumes the characteristic cone shape (keratoconus) .

Using the biomicroscope there may be noted a considerable reduction in the corneal thickness at the top of keratoconus. Over time, the top of keratoconus becomes opaque on account of an alteration in the nutriment of that part of the cornea, which in the most acute forms can present a corneal curvature of more than 62D and reach a corneal thickness of even 446 μm. If the disease is neglected, the top can ulcerate with consequent perforation of the cornea; there appear pain, lacrimation and spasm of the eyelids. These changes of the cornea due to keratoconus produce an alteration in the disposition of the corneal protein, causing micro-scars that further distort the images and in some cases prevent passage of light, thus giving rise to a troublesome dazzling feeling, above all at times of the day when the Sun is low on the horizon (sunrise and sunset) . As already mentioned, in order to correct the visus it becomes necessary to change spectacles frequently. Only after the use of spectacles has proven unsatisfactory, in milder forms rigid contact lenses may be applied.

The real problem arises when the cornea affected by keratoconus undergoes considerable thinning or if cicatrization occurs following upon lacerations of the corneal surface, rendering necessary even surgical transplantation of the cornea (keratoplasty) .

In 2002 so-called lamellar keratoplasty was introduced in Italy for the treatment of keratoconus, whereby, in practice, not the entire cornea is replaced, but only the outer thickness, i.e., the part affected by the disease.

However, already by 1997 in Germany, in the ophthalmic clinic of the Carl Gustaw Carus University of Dresda, a new safer and less invasive technique was developed, referred to as "corneal cross-linking", which uses in particular riboflavin, activated by a UV laser; in 2005 this technique was tested also in Italy and is by now widely used successfully in various Italian eye clinics.

Corneal cross-linking is a low-invasive method, which uses riboflavin activated by a UV laser (366 nm) ; said method is painless and is carried out in day- hospital. Cross-linking enables reinforcement of the structure of the cornea affected by keratoconus through the interweaving and increase in links (cross-linking) between the fibres of the corneal collagen. From the clinical studies conducted, this method has proved able to reduce the astigmatism associated to keratoconus as well as to slow down or arrest evolution of keratoconus,. thus avoiding the need for transplantation of the cornea. Also other disorders characterized by corneal ecstasia benefit from treatment using the cross-linking method. Corneal cross-linking is carried out by applying a local corneal anaesthesia for making the abrasion of the corneal epithelium (de-epithelization) having a

diameter of 8-9 mm. This is followed by a frequent instillation of a 0.1% riboflavin-based ophthalmic solution followed, after 15 minutes, by irradiation with ultraviolet (UV-A) emitter for 5 minutes, and then by new instillation and new irradiation for a total of 6 cycles (30 minutes in all) .

Riboflavin, in particular riboflavin phosphate, which is commonly used in corneal cross-linking, is a hydrophilic photosensitizing and photopolymerizing molecule with a poor capacity for diffusing through the epithelium and hence reaching the corneal stroma. It is therefore necessary to facilitate absorption thereof and complete imbibition of the corneal stroma before starting the irradiation with UV-A, by means of removal of the corneal epithelium (de-epithelization) . This procedure can create, albeit rarely, complications at a corneal level, pain, in addition to being a method that renders the task of the oculist more difficult.

It would hence be desirable to improve the absorption of riboflavin, without having to resort to de-epithelization of the cornea, hence obtaining a noninvasive corneal cross-linking with elimination or reduction of the anaesthesia and consequent fast healing without pain or possible complications. It would moreover be desirable to envisage compounds that enable ease of epithelial absorption but are provided with equal or higher activity than riboflavin in determining photosensitization and photopolymerization of the collagen fibrils; said compounds should preferably be activated at intensities of light close to the visible in order to overcome the harmful effects of the repeated cycles of UV radiation necessary for activation of riboflavin. It has now been surprisingly discovered that by administering on the cornea ophthalmic compositions containing enhancers chosen from among: bio-enhancers (i.e., substances that favour the passage of riboflavin or of other photosensitizing and photopolymerizing substances through the corneal epithelium, enabling absorption by the corneal stroma itself) , such as for example EDTA, sodium EDTA, potassium EDTA, polysorbate 80, tromethamine, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium chloride, lauric acid, menthol, methoxysalicylate, polyoxyethylene, sodium glycholate, sodium glycodeoxycholate, sodium lauryl sulphate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate; and/or photo-enhancers (i.e., photosensitive and photopolymerizing substances that can be readily absorbed by the epithelium and that, like riboflavin, can also be activated by light to form corneal cross- linking) , such as for example the dyes acridine yellow, quinidine yellow, methylene blue, and erythrosine, the structures of which are given below: acridine yellow: useful absorption: 460 nm

Figure imgf000007_0001

quinidine yellow

Figure imgf000007_0002

methylene blue useful absorption: 668 nm

Figure imgf000007_0003
erythrosine B

2 ' , 4 ' , 5 ' , 7 '-Tetraiodofluorescein disodium salt

Absorption: 525 nm

Figure imgf000008_0001

Molecular formula: C20H6I4Na2O5

Molecular weight: 879.86

possibly associated to riboflavin, an improved corneal cross-linking is obtained by means of an irradiation close to the visible that is less harmful, without any need for de-epithelization.

The present invention hence envisages the use of the enhancers described above, either alone or variously mixed together, possibly with riboflavin, for the preparation of ophthalmic compositions to be used for cross-linking in keratoconus or in other corneal ectasias .

The enhancers according to the present invention can be used for application directly on the cornea for cross-linking of keratoconus or other corneal ectasias without proving cytotoxic.

Forming a further subject of the present invention are ophthalmic compositions containing the enhancers mentioned above possibly associated to riboflavin; said ophthalmic composition can be prepared according to known techniques and can contain in particular: one or more bio-enhancers with one or more photo-enhancers and possibly riboflavin; one or more bio-enhancers with possibly riboflavin; one or more photo-enhancers with possibly riboflavin.

After ocular administration of the compositions described above containing just one or more bio- enhancers or else one or more photo-enhancers, there may possibly be applied directly on the cornea a solution of one or more photosensitizing and photopolymerizing substances, in particular riboflavin.

The bio-enhancers of the present invention are present in appropriate amounts in all the compositions described above chosen between 0.001 wt% and 5 wt% with respect to the composition.

In particular the enhancer capability depends above all from the EDTA and tromethamine association since the two compounds form together a ion-pair between the EDTA non salified carboxyl and the tromethamine which has a notable membrane penetrative capacity.

It has been pointed out from the search results that if the tromethamine is preferably present at between 0.05 wt% and 0.5 wt%, and EDTA is preferably present at between 0.05 wt% and 0.5 wt%, the riboflavin absorption is immediate.

The photosensitizing and photopolymerizing substances (photo-enhancers) , amongst which riboflavin, of the present invention are used in appropriate amounts chosen between 0.001 wt% and 1 wt% with respect to the composition.

In addition, the riboflavin preferably used in the present invention is riboflavin phosphate in appropriate amounts in all the compositions described above; in particular it is preferably present at between 0.05 wt% and 0.3 wt% of the composition of the present invention.

The ophthalmic compositions of the present invention can be prepared in the technical form of collyriums, eye-drops, eye-washes, ointments, and in any case in all the pharmaceutical technical forms that enable a corneal application according to known techniques; given hereinafter are examples provided by way of illustration, without this implying any limit to the present invention.

In each example, the dosage of the individual components is expressed in weight percentage.

EXAMPLE 1

Figure imgf000011_0001

EXAMPLE 2

Figure imgf000011_0002
EXAMPLE 3
Figure imgf000012_0001

EXAMPLE 4

Figure imgf000012_0002
EXAMPLE 5
Figure imgf000013_0001

EXAMPLE 6

Figure imgf000013_0002
EXAMPLE 7
Figure imgf000014_0001

EXAMPLE 8

Figure imgf000014_0002
EXAMPLE 9
Figure imgf000015_0001

Note that, when the concentration of tromethamine is increased, it is necessary to increase NaHaPO4 sufficiently so as to guarantee a pH of 7-7.2.

EXAMPLE 10

Figure imgf000015_0002
EXAMPLE 11
Figure imgf000016_0001

EXAMPLE 12

Figure imgf000016_0002
EXAMPLE 13

Figure imgf000017_0001

It should be pointed out that the formulations 1- 13 may also be isotonic or even hypertonic with the addition of sufficient sodium chloride (or other osmolyte) to achieve said purpose.

Claims

1. Use of one or more enhancers chosen between bio-enhancers and/or photo-enhancers, possibly associated to riboflavin, for the preparation of ophthalmic compositions for the method of corneal cross-linking in the treatment of the keratoconus or of other ectasic disorders.
2. Use according to Claim 1, wherein the bio- enhancers, either alone or mixed together, are chosen from among EDTA, sodium EDTA, potassium EDTA, polysorbate 80, tromethamine, azone, benalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium chloride, lauric acid,
, menthol, methoxy salicylate, polyoxyethylene, sodium glycholate, sodium glycodeoxycholate, sodium lauryl sulphate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate .
3. Use according to either Claim 1 or Claim 2, wherein the bio-enhancers are present in an amount chosen between 0.0001-5 wt% with respect to the composition, in particular EDTA is between 0.001 and 1 wt%, tromethamine is between 0.001 and 2 wt%, and polysorbate 80 is between 0.001 and 5 wt% .
4. Use according to Claim 3, wherein EDTA is present in an amount between 0.05 and 0.5 wt% and/or tromethamine in an amount between 0.05 and 0.5 wt%.
5. Use according to any one of Claims 1 to 4, wherein the photo-enhancers are chosen from among the dyes: acridine yellow, quinidine yellow, methylene blue, erythrosine.
6. Use according to any one of Claims 1 to 5, wherein the photo-enhancers are present in an amount of between 0.001 and 1 wt%, and riboflavin phosphate is possibly present in an amount of between 0.05 and 0.3 wt%.
7. Use according to any one of Claims 1 to 6, wherein riboflavin phosphate is possibly present in an amount of between 0.05 and 0.3 wt%.
8. A composition for the use according to any one of Claims 1 to 7, wherein one or more bio- enhancers are present with one or more photo- enhancers and possibly riboflavin.
9. The composition for the use according to any¬ one of Claims 1 to I1 wherein one or more bio- enhancers are present possibly with riboflavin.
10. The composition for the use according to any¬ one of Claims 1 to 7, wherein one or more photo- enhancers are present possibly with riboflavin.
11. A collyrium for the use according to any one of Claims 1 to 7 for the treatment of keratoconus or other ectasic disorders with the method of corneal cross-linking.
PCT/IT2009/000392 2008-08-28 2009-08-27 Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders WO2010023705A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
ITRM2008A000472A IT1393402B1 (en) 2008-08-28 2008-08-28 Using possibly enhancer with riboflavin as well as' relative ophthalmic compositions for corneal cross-linking of keratoconus or other corneal pathologies estasia
ITRM2008A000472 2008-08-28

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
ES09748494.3T ES2460578T3 (en) 2008-08-28 2009-08-27 Use of EDTA + tromethamine or photo-enhancers, associated with riboflavin, for corneal cross-linking in the treatment of keratoconus or other ectatic corneal disorders
JP2011524534A JP2012500844A (en) 2008-08-28 2009-08-27 Use of an enhancer capable of associating with riboflavin and the corresponding ophthalmic composition for corneal cross-linking in the treatment of keratoconus or corneal dilatation
EA201100393A EA022055B1 (en) 2008-08-28 2009-08-27 Use of bio-enhancers for corneal cross-linking
MX2013013707A MX358176B (en) 2008-08-28 2009-08-27 Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders.
CN200980138188.3A CN102164592B (en) 2008-08-28 2009-08-27 The reinforcing agent that can use together to riboflavin is for the preparation of carrying out the purposes of ophthalmic composition of corneal cross-linking and corresponding ophthalmic composition in the treatment of keratoconus
DK09748494.3T DK2323642T3 (en) 2008-08-28 2009-08-27 Use of EDTA + tromethamine or photo-enhancers in association with riboflavin for corneal cross-linking in the treatment of keratoconus or other ectatic corneal disorders
KR1020117006855A KR20110046567A (en) 2008-08-28 2009-08-27 Corresponding ophthalmic compositions for the use of enhancers, possibly associated with riboflavin, and for corneal crosslinking in the treatment of keratoconus or other corneal dilatation diseases.
PL09748494T PL2323642T3 (en) 2008-08-28 2009-08-27 Use of EDTA+tromethamine or of photoenhancers, associated to riboflavin for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders
EP09748494.3A EP2323642B1 (en) 2008-08-28 2009-08-27 Use of EDTA+tromethamine or of photoenhancers, associated to riboflavin for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders
AU2009286285A AU2009286285B2 (en) 2008-08-28 2009-08-27 Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders
BRPI0910368A BRPI0910368A2 (en) 2008-08-28 2009-08-27 "use of one or more enhancers chosen from biointensifiers and photo intensifiers, composition for use of one or more enhancers chosen from biointensifiers and photo intensifiers and eye drops for use of one or more intensifiers chosen from biointensifiers and photo intensifiers"
MX2011002234A MX2011002234A (en) 2008-08-28 2009-08-27 Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders.
IL211448A IL211448A (en) 2008-08-28 2011-02-27 Use of bio-enhancers and/or photo-enhancers for preparing ophthalmic compositions comprising riboflavin or riboflavin phosphate for treating corneal ectasic disorders by corneal cross-linking
US13/036,492 US20110152219A1 (en) 2008-08-28 2011-02-28 Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders

Related Child Applications (1)

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US13/036,492 Continuation-In-Part US20110152219A1 (en) 2008-08-28 2011-02-28 Use of enhancers, possibly associated to riboflavin, as well as corresponding ophthalmic compositions for corneal cross-linking in the treatment of the keratoconus or of other corneal ectasic disorders

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US (1) US20110152219A1 (en)
EP (1) EP2323642B1 (en)
JP (1) JP2012500844A (en)
KR (1) KR20110046567A (en)
CN (1) CN102164592B (en)
AU (1) AU2009286285B2 (en)
BR (1) BRPI0910368A2 (en)
DK (1) DK2323642T3 (en)
EA (2) EA022055B1 (en)
ES (1) ES2460578T3 (en)
IL (1) IL211448A (en)
IT (1) IT1393402B1 (en)
MX (2) MX2011002234A (en)
PE (1) PE20110287A1 (en)
PL (1) PL2323642T3 (en)
PT (1) PT2323642E (en)
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WO2012095877A1 (en) * 2011-01-12 2012-07-19 Sooft Italia Spa Corneal delivery of cross-linking agents by iontophoresis for the treatment of keratoconus and related ophthalmic compositions
WO2012158991A2 (en) * 2011-05-18 2012-11-22 Avedro, Inc. Controlled application of cross-linking agent
US8366689B2 (en) 2008-09-30 2013-02-05 Avedro, Inc. Method for making structural changes in corneal fibrils
ITRM20110560A1 (en) * 2011-10-25 2013-04-26 Sooft Italia Spa Improved composition of cross-linking for the treatment of keratoconus by means of iontophoresis
US8545487B2 (en) 2007-12-05 2013-10-01 Avedro Inc. Eye therapy system
US8574277B2 (en) 2009-10-21 2013-11-05 Avedro Inc. Eye therapy
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US9020580B2 (en) 2011-06-02 2015-04-28 Avedro, Inc. Systems and methods for monitoring time based photo active agent delivery or photo active marker presence
US9044308B2 (en) 2011-05-24 2015-06-02 Avedro, Inc. Systems and methods for reshaping an eye feature
EP2830627A4 (en) * 2012-03-29 2015-10-14 Cxl Ophthalmics Llc Ocular treatment solutions, delivery devices and delivery augmentation methods
CN105256059A (en) * 2015-11-20 2016-01-20 山东省眼科研究所 Application of TUBA3D gene in preparing keratoconus diagnosis product
WO2016174688A1 (en) 2015-04-29 2016-11-03 Sooft Italia Spa Improved cross-linking agents of collagen fibers for the use in the treatment of corneal ectasia
US9498114B2 (en) 2013-06-18 2016-11-22 Avedro, Inc. Systems and methods for determining biomechanical properties of the eye for applying treatment
US9498122B2 (en) 2013-06-18 2016-11-22 Avedro, Inc. Systems and methods for determining biomechanical properties of the eye for applying treatment
US9555111B2 (en) 2012-03-29 2017-01-31 Cxl Ophthalmics, Llc Ocular cross-linking system and method for sealing corneal wounds
US9566301B2 (en) 2012-03-29 2017-02-14 Cxl Ophthalmics, Llc Compositions and methods for treating or preventing diseases associated with oxidative stress
US9622911B2 (en) 2010-09-30 2017-04-18 Cxl Ophthalmics, Llc Ophthalmic treatment device, system, and method of use
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